Recent advances in neonatal care have greatly increased the survival rate of preterm births and infants suffering from asphyxia or hypoxic-ischemic (HI) brain injury. However, as high as 37% infants with intrauterine or neonatal insults still developed long-term neurodevelopmental deficits (Lancet 2012; 379: 445-52, Ref #74). Hence, it remains an important task to improve brain protection strategies against neonatal HI injury. Hypoxia Inducible Factor-1a (HIF1a), a key regulator of cellular adaptation to hypoxia and oxidative stress, ameliorates adult cerebral ischemia and myocardial infarction injury, but its roles in birth asphyxia and perinatal HI remain unclear. In this R21 proposal, we will test the hypothesis that intranasal delivery of GSK360A, a potent PHD inhibitor, produces CNS-specific stabilization of HIF1a to oppose neonatal HI brain injury. Moreover, deficient HIF1a expression by oligodendrocyte progenitors (OPC) and early oligodendrocytes (pre-OL) is an important contributor to selective white-matter vulnerability in perinatal HI brain injury. We will test our hypothesis in three specific aims: Aim 1: Examine the functions of HIF1a and its key effectors that may protect OLs in vitro Aim 2: Test the effects of OPC/pre-OL expression of stable HIF1a in neonatal HI brain injury Aim 3: Determine the effects of intranasal delivery of PHD inhibitors against neonatal HI injury In summary, this exploratory R21 project uses genetic and pharmacological strategies to investigate the roles of HIF1a in neonatal HI brain injury and preferential WM vulnerability. Positive outcomes of this project will shed new insights into the roles of HIF1a in neonates and suggest a novel strategy for brain protection in newborns.